Int J Biol Sci 2014; 10(5):530-542. doi:10.7150/ijbs.8450 This issue
1. Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA;
2. Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA;
3. Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA;
4. Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University School of Medicine, Kagawa 761-0793, Japan;
5. Department of Pharmacology, Kagawa University School of Medicine, Kagawa 761-0793, Japan;
6. Department of Nephrology and Hypertension, Osaka City General Hospital, Osaka 534-0021, Japan.
In the intrarenal renin-angiotensin system, angiotensinogen levels are well known to be increased in diabetes, and these enhanced intrarenal angiotensinogen levels may initiate the development and accelerate the progression of diabetic nephropathy. However, the specific localization of the augmented angiotensinogen in proximal tubule segments in diabetes is still unknown. We investigated the detailed localization of angiotensinogen in 3 proximal tubule segments in the diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and the control Long-Evans Tokushima Otsuka (LETO) rats. We also prepared OLETF rats treated with angiotensin II type 1 receptor blocker, olmesartan or with a combination of vasodilator agents. Moreover, biopsied samples of human kidney cortex were used to confirm the results of animal studies. We examined the co-localization of angiotensinogen with segment-specific markers by double staining using fluorescence in situ hybridization and/or immunofluorescence. Angiotensinogen mRNA expression was barely detectable in segment 1. In segment 3, the area of angiotensinogen mRNA expression was augmented in the OLETF rats compared with the LETO rats. Angiotensinogen protein expression areas in segments 1 and 3 were also increased in the OLETF rats compared with the LETO rats. Chronic treatment with olmesartan ameliorated these areas of augmented angiotensinogen expression. Biopsied human kidney samples showed similar results. These data suggest that the augmented angiotensinogen mRNA levels in segment 3 and angiotensinogen protein levels in segments 1 and 3 may contribute to the progression of diabetic nephropathy.
Keywords: angiotensin II receptor blocker, angiotensinogen, diabetic nephropathy, proximal tubule, renin-angiotensin system.